β1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: Protective role of S1PR1 cardiac gene therapy

Alessandro Cannavo, Giuseppe Rengo, Daniela Liccardo, Gennaro Pagano, Carmela Zincarelli, Maria Carmen De Angelis, Roberto Puglia, Elisa Di Pietro, Joseph E. Rabinowitz, Maria Vittoria Barone, Plinio Cirillo, Bruno Trimarco, Timothy M. Palmer, Nicola Ferrara, Walter J. Koch, Dario Leosco, Antonio Rapacciuolo

Research output: Contribution to journalArticle

Abstract

BACKGROUND - The sphingosine-1-phosphate receptor 1 (S1PR1) and β1-adrenergic receptor (β1AR) are G-protein-coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Importantly, both of these receptors can be regulated by the actions of G-protein-coupled receptor kinase-2, which triggers desensitization and downregulation processes. Although classic signaling paradigms suggest that simultaneous activation of β1ARs and S1PR1s in a myocyte would simply result in opposing action on cAMP production, in this report we have uncovered a direct interaction between these 2 receptors, with regulatory involvement of G-protein-coupled receptor kinase-2. METHODS AND RESULTS - In HEK (human embryonic kidney) 293 cells overexpressing both β1AR and S1PR1, we demonstrated that β1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a β-adrenergic receptor agonist) treatment. This cross talk between these 2 distinct G-protein-coupled receptors appears to have physiological significance, because they interact and show reciprocal regulation in mouse hearts undergoing chronic β-adrenergic receptor stimulation and in a rat model of postischemic heart failure. CONCLUSIONS - We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious β1AR overstimulation in heart failure.

Original languageEnglish
Pages (from-to)1612-1622
Number of pages11
JournalCirculation
Volume128
Issue number15
DOIs
Publication statusPublished - Oct 8 2013

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Keywords

  • Genetic therapy
  • Heart failure
  • Hypertrophy
  • Receptors, adrenergic, beta
  • Signal transduction

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Cannavo, A., Rengo, G., Liccardo, D., Pagano, G., Zincarelli, C., De Angelis, M. C., Puglia, R., Di Pietro, E., Rabinowitz, J. E., Barone, M. V., Cirillo, P., Trimarco, B., Palmer, T. M., Ferrara, N., Koch, W. J., Leosco, D., & Rapacciuolo, A. (2013). β1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: Protective role of S1PR1 cardiac gene therapy. Circulation, 128(15), 1612-1622. https://doi.org/10.1161/CIRCULATIONAHA.113.002659